: This application presents a rigorous program of patient-oriented research and mentoring. The P.I. is a Hispanic physician-investigator with a substantial track record in data-based, hypothesis-driven patient-oriented investigation and mentoring. As Director of the UCLA Graduate Training Program in Translational Investigation, Associate UCLA GCRC Program Director, and Editor of two Nature Publishing Group journals, Molecular Psychiatry and The Pharmacogenomics Journal, the P.I. is uniquely qualified to provide clinical research training and to mentor young clinical investigators. This award would support his efforts to develop new mentoring programs both in the P.I. 's own area of research and in the core components of clinical research. This includes mentoring in the fundamental skills, methodology, theories, and conceptualizations necessary for the well-trained, independent, clinical researcher. Specifically, the P.I. will mentor young investigators in the design of clinical research projects, hypothesis development, clinical pharmacology and pharmacogenomics, scientific writing, and the legal, ethical and regulatory issues related to clinical research. Issues that are particularly relevant to research and of general interest to those in the early stages of their careers include the training of minority clinical researchers and the conduction of research in ethnically identified minority populations. The research proposal tests the hypothesis that leptin contributes to the regulation of the dynamics of human neuroendocrine function. This hypothesis will be tested by a carefully designed, prospective clinical study of the rapidly-sampled dynamics of endocrine rhythms during the course of leptin-replacement treatment in the only three adult individuals identified so far who are leptin-naive due to a functional leptin gene mutation. We will study their endocrine function at baseline, and during the course of leptin treatment, and compare it to obese subjects who are not leptin deficient. The P.I. has previously worked with those patients. They are member of a large, extended, highly consanguineous pedigree, are morbidly obese, and present with endocrine dysfunction. To test the hypothesis that leptin impacts on the dynamics of human neuroendocrine function, we propose a series of prospective, longitudinal, rapid-sampled, 24-h endocrine studies during the course of leptin replacement therapy in those patients and in three ethnically-defined control groups. The confirmation of our hypothesis may have two consequences. For the understanding of biology, it will indicate that leptin contributes to regulate a key function of the central nervous system, which is neuroendocrine homeostasis. This work may reveal new sites of leptin action with potential therapeutic value.